Maternal programming is a term that describes the action of maternal factors during sensitive periods of development that produces persistent effects in the offspring. For example, nutrient availability in the maternal environment has a major impact on fetal growth and later later-life metabolic and mental health. Also, a stressful maternal environment can alter offspring responsiveness to stress, and the quality of maternal care influences the cognitive and emotional development of the offspring. We have identified a novel programming paradigm using a mouse model in which maternal voluntary activity/exercise (in large cages with running wheels) vs. sedentary life (in standard cages) during the postpartum period improves a number of cognitive, emotional and social behaviors of the offspring. Since voluntary wheel running suppresses the production of proinflammatory cytokines associated with the low grade inflammation of sedentary animals, we extended the model by further increasing maternal inflammation by bacterial lipopolysaccharide (LPS), which worsened offspring behaviors. Therefore, dams in cages with running wheels approximate mothers with normal postpartum period, while dams in standard cages and LPS-injected dams in cages with wheels represent mothers with postpartum complications of low grade inflammation (associated with obesity and psychiatric disease) and frank inflammation (as a result of peripartum infection). Although the long-term beneficial effect of exercise in individual is well known, to the best of our knowledge, our study is the first that implicates an intergenerational effect of maternal exercise during the postpartum period on behavior. Preliminary data suggest that this programming is mediated by milk cytokines and growth factors and therefore we refer to it as lactocrine behavioral programming. Our working model is that sedentary conditions and the associated low grade inflammation during lactation, imposed by standard laboratory housing, as well as maternal systemic inflammatory conditions, result in complex changes in the cytokine/growth factor composition of the milk, which lead to changes in offspring immune system development. This in turn alters the offspring epigenome at environmentally sensitive domains we recently identified in hippocampal and cortical neurons. Because of the association of epigenetic domains with synaptic genes, neurons undergo structural changes that alter their connectivity and function and ultimately behavior. This proposal will specify the milk cytokine/immunological link, connecting the postpartum mother with the developing offspring (Aim 1), the impact of the maternal effect on the offspring epigenome (Aim 2), and the neuron structural basis of the behavioral changes in the offspring (Aim 3).